Insect-borne infectious diseases such as malaria affect at least 1 billion people worldwide, and over 1.5 million of these infected individuals die each year. Malarial parasites and many other vector-borne pathogens have developed resistance to current drugs, and vaccines are not available or feasible for many of these pathogens. Insect vector control programs have historically been an effective strategy for reducing disease transmission. However, some of these diseases have remained intractable while others have become resurgent. For this proposal, Cambria Biosciences, an innovative applied genomics biotechnology company, and Dow Agrosciences, a global agrochemical company, are combining their considerable expertise and resources with the ultimate aim of discovering new environmentally sound and effective insecticides that can be incorporated into integrated insect vector management programs for public health. This project will exploit a potent insecticidal natural product, spinosyn A, an active ingredient in the commercially successful insecticide formulation Spinosad, which has been used safely on over 150 crops worldwide and has received the EPA Presidential Green Chemistry Award. Spinosyn A is also very active against mosquitoes, but is toxic to non-target aquatic organisms. The goal of this project is to identify compounds that possess the favorable mosquitocidal attributes of spinosyn A, but a greater degree of species-specificity and attractive formulation characteristics. The specific aims for Phase I (Years 1-2) of this project are: (1) functional expression of the spinosyn A primary target suitable for high-throughput screening, and (2) to identify and express additional genetically validated targets of spinosyn A action. Subsequent specific aims for Phase II (Years 3-4) will be: (1) to develop a high-throughput cell-based assay incorporating the validated targets from the malarial vector Anopheles gambiae, and (2) to implement pilot and large-scale chemical screens for active compounds, involving the extensive assay and chemical library resources of the applicant organizations. This combination of state-of-the-art dipteran genomics and agrichemical high-throughput screening is a highly promising multidisciplinary approach for discovering and developing new products that are desperately needed for the global control of human disease vectors.